Carcinogenesis

Question 1

found in all progeny, begins the process towards malignant transformation

Answer 1

Initiating mutation
- Essentially the first driver mutation
- Often include loss-of-function mutations in genes that maintain genomic integrity

Question 2

mutation that increases
malignant potential of the cell

Answer 2

Driver mutation

Question 3

mutation with low malignant
effect

Answer 3

Passenger mutation

Question 4

Mutations that result in the attributes of malignant cells include:

Answer 4

excessive growth, local invasion, distant
metastasis

Question 5

Gain-of-function mutations

Answer 5

increasing in function - functioning more than it typically would in a normal person
Proto-oncogenes

Question 6

Generally loss-of-function mutations

Answer 6

Tumour suppressor genes

Question 7

class of mutated genes that can be gain- or loss-of-function

Answer 7

Genes regulating apoptosis

Question 8

what class of mutated genes are genes responsible for DNA repair?

Answer 8

• Generally loss of function
• Affected cells acquire mutations at an accelerated rate (aka genomic instability)

Question 9

Once established, tumours evolve genetically based on ____________. This results in tumour cells being genetically ______________.

Answer 9

survival/selection of the fittest (only the best mutations win)

• Resulting in tumour cells being genetically heterogeneous

Question 10

Tumour subclones compete for access to _________ with the fittest subclones dominating tumour mass

Answer 10

nutrients

As a result, tumours become more aggressive over time

Question 11

Tumours that recur after therapy are almost always found to be _________ to the initial treatment

Answer 11

resistant

Question 12

what type of mutation class promotes excessive cell growth, even in the absence of normal growth-promoting signals

Answer 12

Mutation class - Oncogenes

Question 13

how are oncogenes created?

Answer 13

• created by mutations in proto-oncogenes (unmutated cellular counterparts)

Question 14

genes that normally help cells grow and divide to make new cells, or to help cells stay alive.

Answer 14

Proto-oncogenes

Question 15

growth factors or their receptors, signal transducers, transcription
factors, or cell cycle components

Answer 15

can be mutated and become an oncogene

Question 16

• Ras
• PI3 K
• Myc
• Cyclins and cdks
  are all examples of?

Answer 16

proto-oncogenes

Question 17

BRAF - point mutation, translocation - melanomas, leukemias, colon carcinoma and others

Answer 17

RAF

Question 18

Transcriptional activators - translocation - Burkitt lymphoma

Answer 18

MYC

Question 19

CCND1

Question 20

CDK4

Question 21

Downstream component of receptor tyrosine kinases signaling pathways

Answer 21

RAS

Question 22

what is the single most
common abnormality of proto-oncogenes in human tumors

Answer 22

Point mutation of RAS family genes

Question 23

RAS causes
____ of pancreatic adenocarcinomas and
cholangiocarcinomas

____ of colon, endometrial, and thyroid cancers

____ of lung adenocarcinomas and myeloid leukemias

Answer 23

90%
50%
30%

Question 24

Important downstream signaler for lots of growth factors. What are some examples?

Answer 24

RAS
* EGF, PDGF, and CSF-1

Question 25

Ras leads to the activation of what? This induces what type of transcription factors

Answer 25

Ras leads to the activation of MAP kinase which induces MYC MYC induces cyclin, more cyclin = less checkpoints resulting it increased cell proliferation

Question 26

What does PI3 induce?

Answer 26

AKT

Question 27

what does AKT do?

Answer 27

AKT can promote cell cycle progression by activating cyclin A (CDK-1 for S phase) and cyclin D = increase in checkpoints

Question 28

what does AKT decrease/inactivate?

Answer 28

p21 and p27 these are important for inhibiting cyclins (inhibits apoptosis)

Question 29

Immediate early response gene. Induced by Ras/MAPK signaling

Answer 29

MYC (transcription factor)

Question 30

when increased, what does MYC do?

Answer 30

Increases cell proliferation & growth Contributes of other hallmarks of cancer - Warburg effect (eg. can upregulate glycolytic enzymes) - increased telomerase activity (contributes to endless replicative activity) - May also allow more terminally differentiated cells to gain characteristics of stem cells

Question 31

what is the Warburg effect

Answer 31

glycolytic enzymes are upregulated - in this case, cancer cells choose pyruvate to lactic acid pathway for energy even though there is an abundance of oxygen

Question 32

increase _________ activity contributes to endless replicative activity

Answer 32

telomerase

Question 33

MYC is implicated in cancers of (3)

Answer 33

breast, colon, lung

Question 34

Which of the two cell cycle checkpoints regulated by CDK-cyclin complexes do you suppose is more important in cancer?

Answer 34

G1/S - is the start transition - if you can get it going and going rapidly, then it allows for more success MORE mutations will be affiliated with the aspects that are checked at G1/S

Question 35

Products of _________________ apply brakes to cell proliferation. Therefore, abnormalities lead to..?

Answer 35

tumour suppressor genes lead to failure of growth inhibition

Question 36

Rb, P53 and CKIs are examples of which mutation class gene?

Answer 36

Mutation class - Tumour suppressor genes

Question 37

Activation of oncogenes isn’t enough for cancer induction, usually requires loss of _____________ genes as well

Answer 37

tumour suppressor

Question 38

in a normal cell, RB and p52 recognize genotoxic stress and respond by...

Answer 38

responds by shutting down proliferation

Question 39

RB

Question 40

CDKN2A

Question 41

TP53

Answer 41

the guardian of the genome

Question 42

Which tumour suppressor gene functions as a key negative regulator of the G1/S checkpoints

Answer 42

RB

Question 43

when is RB in its active form?

Answer 43

when it is hypophosphorylated

Question 44

what E2F induce?

Answer 44

transcription factors in the S phase

Question 45

what form is RB in to facilitate passing through the G1/S checkpoint?

Answer 45

hyperphosphorylated (inactive)

Question 46

what is gene considered the guardian of the genome and codes for p53 protein. This is also the most frequently mutated gene in human cancer

Answer 46

* TP53

Question 47

what is the function of TP53?

Answer 47

Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis

Question 48

what is P53 usually bound to?

Answer 48

Mdm2

Question 49

what does p53 induce synthesis of?

Answer 49

p21 - binds cell cycle progression - p21 binds to CDKS (check-point proteins) to inactive that this stops the cell cycle so that the DNA repair cell can be repaired

Question 50

P53 uses _____ and _____ for successful DNA repair

Answer 50

p21 and GADD45

Question 51

what will occur in a cell with mutations of loss of p53

Answer 51

there will be no cell cycle arrest, no DNA repair, no senescence this will result in mutant cells and ultimately the expansion and additional mutations

Question 52

how does p53 arrest the cell cycle until DNA can be repaired?

Answer 52

p53 induces the synthesis of p21 which binds to and inhibits CDKs - to stop it from working as a result, this stops the cycle cell

Question 53

____ can also be silenced by hypermethylation rather than mutation. This is an example of a ________ change and occurs in some cervical cancers

Answer 53

p16 - by silenced by hypermethylation

Question 54

Inhibits Cdk4- Cyclin D complex (G1-CDK complex) needed for progression through the cell cycle - describes the function of what

Answer 54

p16

Question 55

What do you notice about the common oncogenes and tumour suppressor genes we have discussed?

Answer 55

G1/S start transition

Question 56

At least 1 of the 4 key regulators of the cell cycle is dysregulated in the significant majority of all human cancers

Answer 56

p16, cyclin D, Cdk4, RB

Question 57

The wnt-B-catenin pathway normally promotes

Answer 57

cell-proliferation

Question 58

mutation in APC

Answer 58

excessive activity (gain of function of) of B-catenin

Question 59

All cancers display 8 fundamental changes in cell physiology:

Answer 59

1. Self-sufficiency in growth signals 2. Insensitivity to growth-inhibitory signals 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicative potential 6. Sustained angiogenesis 7. Ability to invade and metastasize 8. Ability to evade the host immune system

Question 60

Cancer cells take up high levels of glucose and demonstrate increased conversion of glucose to lactate. Even in the presence of ample oxygen

Answer 60

Warburg effect

Question 61

Why do you suppose a cancer cell relies on glycolysis alone for ATP production?

Answer 61

it uses the byproduct of glycolysis as the building blocks for quick growth Mitochondrial oxidative phosphorylation does not!

Question 62

cell permanently exits the cell cycle & never divides again

Answer 62

Senescent

Question 63

how can cancer cells evade senescence

Answer 63

- Likely due to loss of functions mutations in p53 and p16 - Allows cell to pass through G1/S checkpoint

Question 64

Cancer cells have also demonstrated the ability to express telomerase. what does this allow the cancer cell to do?

Answer 64

Remember telomerase is only very minimally expressed in most somatic cells replicate indefinitely